The novel SARS-coronavirus 2 (SARS-CoV-2) poses a global challenge on healthcare and society. For understanding the susceptibility for SARS-CoV-2 infection, the cell type-specific expression of the host cell surface receptor is necessary. The key protein suggested to be involved in host cell entry is angiotensin I converting enzyme 2 (ACE2). Here, we report the expression pattern of ACE2 across > 150 different cell types corresponding to all major human tissues and organs based on stringent immunohistochemical analysis. The results were compared with several datasets both on the mRNA and protein level. ACE2 expression was mainly observed in enterocytes, renal tubules, gallbladder, cardiomyocytes, male reproductive cells, placental trophoblasts, ductal cells, eye, and vasculature. In the respiratory system, the expression was limited, with no or only low expression in a subset of cells in a few individuals, observed by one antibody only. Our data constitute an important resource for further studies on SARS-CoV-2 host cell entry, in order to understand the biology of the disease and to aid in the development of effective treatments to the viral infection.

https://www.embopress.org/doi/pdf/10.15252/msb.20209610

The protein expression profile of ACE2 in human tissues.

The novel SARS-coronavirus 2 (SARS-CoV-2) poses a global challenge on healthcare and society. For understanding the susceptibility for SARS-CoV-2 infection, the cell type-specific expression of the host cell surface receptor is necessary. The key protein suggested to be involved in host cell entry is Angiotensin I converting enzyme 2 (ACE2). Here, we report the expression pattern of ACE2 across >150 different cell types corresponding to all major human tissues and organs based on stringent immunohistochemical analysis. The results were compared with several datasets both on the mRNA and protein level. ACE2 expression was mainly observed in enterocytes, renal tubules, gallbladder, cardiomyocytes, male reproductive cells, placental trophoblasts, ductal cells, eye and vasculature. In the respiratory system, the expression was limited, with no or only low expression in a subset of cells in a few individuals, observed by one antibody only. Our data constitutes an important resource for further studies on SARS-CoV-2 host cell entry, in order to understand the biology of the disease and to aid in the development of effective treatments to the viral infection.

https://biorxiv.org/content/10.1101/2020.03.31.016048v1.full.pdf

The protein expression profile of ACE2 in human tissues

AGA Institute Rapid Review of the Gastrointestinal and Liver Manifestations of COVID-19, Meta-Analysis of International Data, and Recommendations for the Consultative Management of Patients with COVID-19.

A Single-Cell RNA Expression Map of Human Coronavirus Entry Factors

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) disease (COVID-19) appears to have a higher mortality rate in presence of comorbidities and in men. The latter suggests the presence of a possible sex-dependent susceptibility. An enzymatic system involved in this different predisposition could be represented by angiotensin converting enzyme 2 (ACE2). ACE2 is activated and down-regulated by the spike protein of the virus and allows the penetration of SARS-CoV-2 into epithelial cells and myocardium. Data on the experimental animal have shown that 17s-estradiol increases the expression and activity of ACE2 in both adipose tissue and kidney. Spontaneously hypertensive male mice have a higher myocardial ACE2 expression than females and its levels decrease after orchiectomy. In addition to this first aspect, the recent evidence of an increased frequency of venous thromboembolism in patients with COVID-19 (a clinical element associated with a worse prognosis) calls the attention on the safety of treatment with testosterone, in particular in hypogonadal men with greater genetic predisposition. Evidence that sex hormones are able to modulate the expression of ACE2 could help in interpreting epidemiological results and in designing more appropriate intervention strategies. Moreover, the vitamin D deficiency in elderly men may be worthy of further study regarding the epidemiological aspects of this different susceptibility and lethality between sexes.

https://www.mdpi.com/1422-0067/21/8/2948/pdf

Sex-Specific SARS-CoV-2 Mortality: Among Hormone-Modulated ACE2 Expression, Risk of Venous Thromboembolism and Hypovitaminosis D.

Since SARS-CoV-2 infection was first identified in December 2019, it spread rapidly and a global pandemic of COVID-19 has occurred. ACE2, the receptor for entry into the target cells by SARS-CoV-2, was found to abundantly express in testes, including spermatogonia, Leydig and Sertoli cells. However, there is no clinical evidence about whether SARS-CoV-2 infection can affect male gonadal function so far. In this study, we compared the sex-related hormones between 81 reproductive-aged men with SARS-CoV-2 infection and 100 age-matched healthy men, and found that serum luteinizing hormone (LH) was significantly increased, but the ratio of testosterone (T) to LH and the ratio of follicle stimulating hormone (FSH) to LH were dramatically decreased in males with COVID-19. Besides, multivariable regression analysis indicated that c-reactive protein (CRP) level was significantly associated with serum T:LH ratio in COVID-19 patients. This study provides the first direct evidence about the influence of medical condition of COVID-19 on male sex hormones, alerting more attention to gonadal function evaluation among patients recovered from SARS-CoV-2 infection, especially the reproductive-aged men.

/pdf/effect-of-sars-cov-2-infection-upon-male-gonadal-function-a-1c8pqib3oo.pdf

Effect of SARS-CoV-2 infection upon male gonadal function: A single center-based study

Abstract Critical coronavirus disease 2019 (COVID-19) is associated with high mortality and potential genetic factors have been reported to be involved in the development of critical COVID-19. We performed a genome-wide association study to identify the genetic factors responsible for developing critical COVID-19. 632 critical patients with COVID-19 and 3021 healthy controls from the Chinese population were recruited. First, we identified a genome-wide significant difference of IL-6 rs2069837 ( p = 9.73 × 10 −15 , OR = 0.41) between 437 critical patients with COVID-19 and 2551 normal controls in the discovery cohort. When replicated these findings in a set of 195 patients with critical COVID-19 and 470 healthy controls, we detected significant association of rs2069837 with COVID-19 ( p = 8.89 × 10 −3 , OR = 0.67). This variant surpassed the formal threshold for genome-wide significance (combined p = 4.64 × 10 −16 , OR = 0.49). Further analysis revealed that there was a significantly stronger expression of IL-6 in the serum from patients with critical COVID-19 than in that from patients with asymptomatic COVID-19. An in vitro assay showed that the A to G allele changes in rs2069837 within IL-6 obviously decreased the luciferase expression activity. When analyzing the effect of this variant on the IL-6 in the serum based on the rs2069837 genotype, we found that the A to G variation in rs2069837 decreased the expression of IL-6, especially in the male. Overall, we identified a genetic variant in IL-6 that protects against critical conditions with COVID-19 though decreasing IL-6 expression in the serum. 

https://www.nature.com/articles/s41392-022-00923-1.pdf

A genetic variant in IL-6 lowering its expression is protective for critical patients with COVID-19

Objective We used public data to analyze the proteomics, metabolomics and transcriptomics characteristics of COVID-19 patients to identify potential therapeutic targets. More importantly, we also collected clinical data for verification to make the analysis results more reliable. Methods Download the serum proteomics and metabolomics data of COVID-19 patients and describe their changes in serum proteins and metabolites, and use bioinformatics analysis methods to identify potential biomarkers and therapeutic targets. Finally, clinical data and experimental data of cell infection were combined for verification. Results It was found that the serum apolipoprotein A1 (APOA1) protein level in COVID-19 patients was down-regulated (log2FC = −0.39, false discovery rate (FDR) < 0.001), and the degree of reduction in the severe group was more significant (kruskal-test p = 2.5e-05). What is more, APOA1 was not only expressed lower in male patients (Wilcox-test p = 0.012), but also negatively correlated with C-reactive protein (CRP, r = −0.37, p = 0.019). The experiment data from SARS-CoV-2 infected cells further showed that the protein and transcript level of APOA1 gradually decreased as the infection time increased, and the transcription level (log2FC = −8.3, FDR = 0.0015) was more down-regulated than protein level (log2FC = −0.95, FDR = 0.0014). More importantly, the collected clinical data also confirmed that APOA1 was down-regulated in COVID-19 patients (kruskal-test p = 0.001), and APOA1 levels are negatively correlated with IL6 (r = −0.396, p = 2.22e-07), D-dimers (DD, r = −0.262, p = 8.19e-04), prothrombin time (PT, r = −0.464, p = 6.68e-10) and thrombin time (TT, r = −0.279, p = 3.46e-04). Conclusion The degree of down-regulation of APOA1 is positively correlated with the severity of COVID-19, and the expression level of APOA1 is negatively correlated with CRP, IL6, DD, PT, TT, and positively correlated with HD and LDL. This indicates that APOA1 may be a key molecule in tandem acute inflammatory response, coagulation abnormalities and cholesterol metabolism disorder in COVID-19, and could be a potential therapeutic target.

https://www.dovepress.com/getfile.php?fileID=77682

APOA1 Level is Negatively Correlated with the Severity of COVID-19

Serosurveillance is crucial in estimating the range of SARS-CoV-2 infections, predicting the possibility of another wave, and deciding on a vaccination strategy. To understand the herd immunity after the COVID-19 pandemic, the seroprevalence was measured in 3062 individuals with or without COVID-19 from the clinic.The levels of SARS-CoV-2 antibody IgM and IgG were measured by the immuno-colloidal gold method. A fusion fragment of nucleocapsid and spike protein was detected by a qualitative test kit with sensitivity (89%) and specificity (98%).The seroprevalence rate for IgM and IgG in all outpatients was 2.81% and 7.51%, respectively. The sex-related prevalence rate of IgG was significantly higher (P < 0.05) in women than men. The highest positive rate of IgM was observed in individuals < 20 years of age (3.57%), while the highest seroprevalence for IgG was observed in persons > 60 years of age (8.61%). Positive rates of IgM and IgG in the convalescent patients were 31.82% and 77.27%, respectively, which was significantly higher than individuals with suspected syndromes or individuals without any clinical signs (P < 0.01). Seroprevalence for IgG in medical staff was markedly higher than those in residents. No significant difference of seroprevalence was found among patients with different comorbidities (P > 0.05).The low positive rate of the SARS-CoV-2 IgM and nucleic acid (NA) test indicated that the SARS-CoV-2 outbreak is subsiding after 3 months, and the possibility of reintroduction of the virus from an unidentified natural reservoir is low. Seroprevalence provides information for humoral immunity and vaccine in the future. 

/pdf/surveillance-of-sars-cov-2-antibodies-of-patients-in-the-3j0hoye0.pdf

Surveillance of SARS-CoV-2 antibodies of patients in the local affected area during Wuhan lockdown

Objective Unilateral primary aldosteronism (PA) includes aldosterone-producing adenoma (APA), unilateral adrenal hyperplasia, and unilateral multiple nodules. The correlation of multiple nodules, especially genotypic and pathological characteristics, remains unknown. KCNJ5 mutation accounts for 60–80% of unilateral PA, so we aimed to explore the correlation of KCNJ5 somatic mutation and CYP11B1/CYP11B2 staining in multiple nodules in unilateral PA. Design and Methods A total of 56 microdissected nodules from 24 patients with unilateral PA were included. We assessed somatic KCNJ5 mutations, immunohistochemistry for aldosterone synthase (CYP11B2)/cortisol synthase (CYP11B1), and histological cellular composition of nodules together with adjacent adrenal cortical statements. Results KCNJ5 mutations were identified in 17 (17/56, 30.4%) nodules from 11 adrenals (11/24, 45.8%). All KCNJ5-mutant nodules were positive for CYP11B2 staining, 6 cases (6/11) had only one KCNJ5-mutant nodular, and the other 5 cases (5/11) had more than one KCNJ5-mutant nodules. Three cases (3/11) had different KCNJ5 mutations in individual nodules. Compared with KCNJ5-positive adrenals, the cortices adjacent to the nodules in KCNJ5-negative adrenals showed significant proliferation (p = 0.004). CYP11B2/CYP11B1 expression patterns revealed great heterogeneity in intensity and range both in KCNJ5-mutant nodules and KCNJ5-WT ones. Conclusion There is great heterogeneity among nodules from patients with unilateral PA. Countable nodules could be considered as multiple APAs, featuring somatic KCNJ5 mutation, positive CYP11B2 staining, and lack of adjacent cortical proliferation in unilateral multiple nodules.

Wen Xie

Papers

Effect of SARS-CoV-2 infection upon male gonadal function: A single center-based study

A genetic variant in IL-6 lowering its expression is protective for critical patients with COVID-19

APOA1 Level is Negatively Correlated with the Severity of COVID-19

Surveillance of SARS-CoV-2 antibodies of patients in the local affected area during Wuhan lockdown

Exploration of KCNJ5 Somatic Mutation and CYP11B1/CYP11B2 Staining in Multiple Nodules in Primary Aldosteronism